An essential role for the hematopoietic transcription factor Ikaros in hypothalamic-pituitary-mediated somatic growth.

Ikaros transcription factors play critical functions in the control of lymphohematopoiesis and immune regulation. Family members contain multiple zinc fingers that mediate DNA binding and homooligomerization or heterooligomerization. Ikaros is abundantly expressed in pituitary mammosomatotrophs, where it deacetylates histone 3 sites on the proximal growth hormone (GH) promoter to silence gene expression. Ikaros-null mice display stunted growth with reduced circulating levels of the GH target factor insulin-like growth factor I (IGF-I). Ikaros-deficient mice have small anterior pituitary glands with a disproportionately reduced somatotroph population. Systemic administration of GH results in increased IGF-I levels and enhanced somatic growth. In contrast, reconstitution with WT lymphocytes was not sufficient to rescue the stunted growth phenotype of Ikaros-deficient mice. Ikaros was identified in mouse hypothalamic arcuate nuclei, where it colocalized with GH-releasing hormone (GHRH); in contrast, Ikaros-null mice lack GHRH immunoreactivity in the hypothalamus. Overexpression of Ikaros enhanced GHRH promoter activity and induced endogenous GHRH gene expression. These findings unmask a wider role for Ikaros in the neuroendocrine system, highlighting a critical contribution to the development of the hypothalamic-pituitary somatotrophic axis.

Ikaros integrates endocrine and immune system development.

Ikaros transcription factors are essential regulators of lymphopoiesis and the development of the immune system. We now show that Ikaros is expressed in hormone-producing pituitary corticomelanotroph cells, where it binds the proopiomelanocortin promoter and regulates endogenous gene expression. Loss of Ikaros in vivo results in contraction of the pituitary corticomelanotroph population, reduced circulating adrenocorticotrophic hormone levels, and adrenal glucocorticoid insufficiency. While hemopoietic reconstitution failed to correct this hormonal deficit, the phenotype of reduced body weight and diminished survival was rescued by systemic glucocorticoid-hormone administration. Given the established immunomodulatory properties of glucocorticoid hormones, these findings reveal a novel role for Ikaros in orchestrating immune-endocrine development and function.

"Honeycomb Golgi" in pituitary adenomas: not a marker of gonadotroph adenomas.

The vacuolar change in Golgi complexes known as "honeycomb Golgi" has been described as the ultrastructural hallmark of a specific tumor that has been called the "female gonadotroph" adenoma of the human pituitary. Recently, a few adenomas presenting with Cushing's disease have been reported to exhibit this feature. To clarify the significance of a "honeycomb Golgi" in the classification of pituitary adenomas, we studied clinically nonfunctioning adenomas with or without "honeycomb Golgi" using immunohistochemistry for adenohypophysial hormones and RT-PCR for the cell-specific transcription factors Tpit that identifies corticotrophs and SF-1 that identifies gonadotrophs. All adenomas were from women. Among 20 adenomas with complete "honeycomb Golgi" change, gonadotrophin subunits were totally immunonegative, but ACTH was positive in a few cells of 12 adenomas. Among eight adenomas with partial vacuolar change of the Golgi complex, five were positive for gonadotrophins and two were positive for ACTH. A subgroup of these lesions were examined by RT-PCR and among eight adenomas with typical "honeycomb Golgi" one case expressed both Tpit and SF-1, probably due to contamination with normal pituitary and another expressed neither Tpit nor SF-1. Of the remaining six cases, Tpit was expressed in two cases and SF-1 in four. These findings indicate that "honeycomb Golgi" change can been seen in corticotroph adenomas as well as gonadotroph adenomas. The reason why this vacuolar change occurs only in females remains to be clarified.

K-FGF mediated transformation and induction of metastatic potential involves altered ornithine decarboxylase and S-adenosylmethionine decarboxylase expression--role in cellular invasion.

Omithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) expression was investigated in NIH-3T3 fibroblasts that secrete K-FGF. Correlations between altered ODC and SAMDC expression and malignant potential were determined. Increased ODC and SAMDC expression was associated with increased expression of both ODC and SAMDC mRNA and enzyme activity levels. Transcriptional and post-transcriptional regulatory mechanisms were found to account for the increased expression of both ODC and SAMDC. Amplification of the ODC gene also played a role. Correlations between the expression of ODC and the invasion ability of the K-FGF overexpressing cells were also found. Additionally, putrescine, which is a cellular polyamine, was found to play a role in determining the nature of the invasive capacity of the K-FGF overexpressing cells. The results of this study which established correlations between alterations in the expression of ODC and SAMDC, the key rate limiting and regulatory activities in the synthesis of cellular polyamines, and malignant potential as a consequence of K-FGF overexpression supports a model which suggests that growth factor modulation of ODC and SAMDC expression is part of the altered growth regulatory program associated with cellular transformation and malignant progression.